5 (10) estrene derivatives



estates son ns'ranrm 3 Allan Campbell, Kalamazoo Township, Kalamazoo(Ionnty, and John Bahcoclr, Portage Township, Kalamazoo Connty, Mich,assignors to The Upjohn Corn= parry, Kalamazoo, a corporation ofMichigan No Brewing. Application September 6, 1955 Serial No. 532,736

The present invention relates to certain steroid compounds and is moreparticularly concerned with novel 175-l1ydroxy-5 l)-estren-3-oneacylates.

The novel compounds of the present invention are represented by thefollowing formula:

Q my wherein Ac is the acyl radical of an organic carboxylic acidcontaining from one to eight carbon atoms, inclusive, and preferably theacyl radical of a hydrocarbon carboxylic acid containing from one toeight carbon atoms, inclusive.

The novel 17fi-hydroxy-5 (10)-estren-3-one acylates may be obtained byacylating in conventional manner the 17/3-l1ydroxy-5(10)-estren-3-one oralternatively by hydrolyzing the corresponding 3-methoxy-2,5(10)-estradien-IZB-ol acylate as shown in detail in the subsequent generaldescription and in the examples.

It is an object of the present invention to provide the novel compounds17/3-hydroxy-5(10)-estren-3-one acylates wherein the acyl group is oforganic carboxylic acid containing from one to eight carbon atoms,inclusive. A more specific object of the instant invention is to provide17fl-hydroxy5(l0)-estren-3-one acylates wherein the acyl group is ofhydrocarbon carboxylic acid containing from one to eight carbon atoms,inclusive. Another object of the present invention is to provide theintermediate new esters, 3-methoxy-2,S(10)- estradien-l75-ol acylateswherein the acyl groups are defined as herein above as of organiccarboxylic acids and more specifically of hydrocarbon carboxylic acidscontaining from one to eight carbon atoms, inclusive. Other objects ofthe invention will be apparent by one skilled in the art to which thisinvention pertains.

The l7,8-hydroxy-5(10)-estren-3-one acylates of this invention have highanabolic and low androgenic activity. Of particular interest is the17,8-hydroxy-5(10)-estren- 3-one 175-acetate having oral anabolicactivity which is six times that of the parent compound, 17,B-hydroxy-5(l0)-estren-3-one. The instant 5(l0)-estren esters are also importantintermediates in the production of other pharmaceutically activel9-normethyl steroids.

The starting materials for the instant invention are17flhydroxy-5(10)-estren-3-one iBirch, J. Chem. Soc. 367 (1950)] and theorganic carboxylic acid esters containing from one to eight carbon atomsof 3-methoxy- 2,5(l0)-estradien-l7fi-ol prepared as shown inPreparations 1 through 3.

In carrying out the process of the present invention,l7fi-hydroxy-5(lF)-estren-3-one is admixed with an acylice ating agentsuch as, for example, ketene, a ketene of a selected acid, an acid suchas formic acid, an acid chloride, an acid bromide, an acid anhydride orother known acylating agents wherein the corresponding acid is anorganic carboxylic acid and in the preferred embodiment of the inventiona hydrocarbon carboxylic acid having from one to eight carbon atoms,inclusive. Among the preferred acylating agents are the anhydrides ofacetic, propionic, butyric, valeric, succinic, maleic and hexanoicacids, the chlorides or bromides of acetic, propionic, butyric, valeric,isovaleric, hexanoic, heptanoic, octanoic, benzoic, anisic, toluic,phenylaceticphenylpropionic, salicylic, nicotinic, piperonic, acidsuccinic acid tartaric, crotonic and the like. In the preferredembodiment of the instant invention, the solvent such as, for example,dioxane, pyridine, or other inert solvents such as benzene, toluene,ether, and the like are used and the reaction mixture is heated at atemperature between about zero degrees centigrade and the boiling pointof the reaction mixture, usually about room temperature for a periodbetween about one-half hour and about 96 hours. The time of reaction issomewhat dependent upon the temperature :at which the reaction iscarried out, the acylating agent, and the ratio of reactants. After thereaction is completed, the mixture is usually quenched in water or amixture of ice and water and the product collected by filtration andpuritied in conventional manner, such as by recrystallization,chromatography, extraction or combinations thereof.

Alternatively 17(3-hydroxy-5(10)-estren-3-one 17 8- acylates may beproduced by esterifying 3-methoxy- 2,5(10) estradien-l7fi-ol by theconventional methods described before and shown in Preparations 1through 3, to obtain the corresponding 3-methoxy-2,5(10)-estradien-l7fi-ol acylates and hydrolyzing this acylate by the methodshown by Wilds et al., J. Am. Chem. Soc. 75, 5366 (1953), using oxalicacid or other mild organic acids, such as acetic, propionic or butyricacid in aqueous methyl alcohol solution. The enol ether is hydrolyzed togive a saturated 3-keto group while the ester group and the 5(10)-doublebond is maintained.

The following preparations and examples will serve to illustrate theprocess and products of this invention, but the said invention is not tobe considered as limited thereto.

PREPARATION 1 3-meth0xy-2,5(10)-estradien-17,8-0l 1 7/3-acetate To asolution of 2.4 grams of 3-methyl-2,5(10)- estradien-17[3-ol in fivemilliliters of pyridine was added 1.5 miilfliters of acetic anhydride.The solution was warmed to about sixty degrees Centigrade for a periodof about one and one-half hours and thereafter poured onto ice. Theprecipitate was collected on a filter and washed thoroughly with water,yielding 2.6 grams (92 percent) of 3-methoxy-2,5(10)-estradien-17B-ol17pacetate which when recrystallized from methanol had a melting pointof to degrees centigrade and a rotation lal +27 degrees (in chloroform).

Analysis.Calcd. for C H O C, 76.30; H, 9.15.

Found: C, 76.08; H, 9.18.

PREPARATION 2 3-meth0xy-2,5 (1 0 -estradien-1 75-01 17o-benz0ate To asolution of 3-methoxy-2,5(lO)-estradien-17fi- 01 in pyridine was aded anexcess of benzoyl chloride.v The solution was maintained at roomtemperature over a period of 16 hours and then poured into excess ofwater and ice. The precipitate was collected on a filter, thoroughlywashed with water and recrystallized to give pure 3-methoxy-2,5(10)-estradien-17fi-ol l7fi-benzoate.

temperature I of melting point andlphysical constants equal to, those 3PREPARATION 3 S-methoxy-ZJ (1 -estradien-1 75-01 1 7 B-ncy lines In thesame manner as Preparations 1 and 2, inclusive, by reacting3-methoXy-2,5(10)-estradien-l7 3-ol with a suitable organic carboxylicacid acylating agent or a hydrocarbon carboxylic acid acylating agent,other representative 3-methoxy2,5(10)-estradien-l7{3'0l 17B-acylates areprepared such as illustratively: 3-rnethoxy- 2,5(10)-estradien-17,6-ol17 6-propionate, butyrate, isobutyrate, valerate, isovalerate,hexanoate, 'heptanoate, octanoate, ti-cyclopentylpropionate,phenylacetate, phenylpropionate, 0-, n p-toluate, cinnamate, gallate,salicylate, anisate, benzenesulfonate, para-chlorobenzenesulfonate,toluenesulfonate, benzenephosphonate, trimethyh acetate,monochloroacetate, dichloroacetate, trichloroacetate-acid quinolinate,nicotinate, piperonate, orthoor meta-chlorobenzoate, Z-furoate,para-'nitrobenzoate, acid succinate, ortho-chloro-para-nitrobenzoate,acid tartrate, dihydrogencitrate, acid maleate, acid fumarate,thioglycollate, 'bromoacetate, cr otonate, fi-methylcrotonate, or thelike; 7 i

EXAMPLE 1 I 7fi-hydroxy-5 (1 0 strand-one 1 7 B acetate A. From3-methoXy-2,5(lO.) estradien-17}3-ol 17B-ace- 7 rate.

To a solution ofr1.5 grams of 3-methoxy 2,5.(.lll)- estradiene-17 3-oll7fi-acetate in. 150 milliliters of methanol was added 2.3 gramsofoxal-ic acid intwenty milliliters of water. vDuring the addition thesolution. was.

graphed through Flon'sil magnesium silicate in the fol lowing manner:twd-lOO-milliliter fractions with Skellysolve B hexanes; twoISO-milliliter.Skellys'olve B-hexane fractions; one IOU-milliliterSkellysolve B hexane fraction containing one-half percent of acetone;three 50- milliliter fractions. of Skellysolve B hexanes containingone-half percent ofacetone; five SO-milliliter fractions of SkellysolveB hexanes containing one percent acetone; three SC -milliliter and nine100 milliliter, fractions of Skellysolve B containing 7 two percentacetone; three IOU-milliliter fractions of Skellys'olve B containingthree percent acetone;- five IOU-milliliter fractions of Skellysolve Bcontaining eight percent acetone; and three 100- milliliter fractions of'Skellysolve B containing twelve percent acetone. Fractions 18 through22 were combined, the solvent was removed and the residue recrystallizedfrom ether pentane yielding 0.8 gram of- 1713- hydroxy-(lO)-estren 3-oneacetate of melting point 138 to 143 and rotation [e1 +152 degrees inchloroform.

Analysis.-Calcd. for C H O C, 75.91; H, 8.92. Found: C, 75.39, 74.95; H,8.78, 8.46. r

i EXAMPLE 2 1 7 3-hydr0xy 5 -estren-3-one acetate from 1 76- hydroxy-5(1 0 .-estrei1-3-0ne To a solution of 05 gram ofl7B-hydroxy-5(10)-estren- S-one in tenmillilitersof redistilled dioxanewas" added 0.5 milliliter of pyridine and (1.4 milliliter of aceticanhydride. The mixture was allowed to stand at room (twenty to thirtydegrees centigrade) for a period; or six :hours whereafter the reactionmixture was poured *onto ice. The precipitate was collected, washed anddried over anhydrous sodium sulfate. The

'material thus obtained was recrystallized from Skellysolve B hexanescontaining two percent acetone to give Q.l gram ofl7B-hydroxy-5(10)-estren-3-one W S-acetate shown in Example 1.

V hydroxy-S (lO)-estren-3-one benzoate.

EXAMPLE 3 1 7,8-hydr0xy-5 (1 0) -estren-3-0ne ph enylpropionate In thesame manner as given in Example 1, 3-methoxy- 2,5(10)-estradien-l7B-olphenylpropionate was hydrolyzed in aqueous methanol in the presence ofoxalic acid to produce l7fl-hydroxy-5(10)-estren-3-0ne phenylpropionate.

In a manner similar to Example 2, 17,8-hydroxy-5 (10)- estren-3-onephenylpropionate could be obtained by esterifyingl7;8-hydroxy-5(10)-estren-3-one with phenylpropionyl chloride.

EXAMPLE 4 17,8hydr0xy-5 (Z 0) -esti'en-3-0ne propionate17,8-hydroxy5(lO)-estren-3=one propionate is also obtained byesterifying in the manner given in Example 2l7fi-hydroxy-5(10)-estren-3-one with propionic anhydride.

EXAMPLE 5 17/3-hydr0xy-5 (10) -estren-3-one butymte In the manner givenin Example 1, hydrolyzing 3-methoxy-2,5(lO)-estradien 17/3-ol butyrate,dissolved in methanol in the presence of oxalic acid, yielded 17/8-hydroxy-S l0 -estren-3-one butyrate.

l7,8-hydroxy-5(10)-estren-3-one butyrate is also obtained by esterifyingin the manner given in Example 2, l7fi'hydroxy5(lO)-estren-3-one withbutyric anhydride.

' A ExAMPLE 6 g 1 -12 ya'roxy-S (1 0)-esfren-3-0'ne vr/ilerate In themanner given in Example 1,. hydrolyzing 3-methoxy-2,5 10)-estradien-l7fi-ol valerate" dissolved in' EXAMPLE 7 1 7 fi-hydroxyd (J0 -estren3on B-cyciopehty lpi qpionate in the manner given in Example 1,hydrolyzing 3 -methoxy-2,5 (.10) -estradien- 1713-01 p ,8-cyclopentylpropionate, dissolved inrnethanc-l in the presence ofoxalicacid, yielded 17fi-hydroxy-5(10)-estren-3one fi-cyclopentylpro pionate.

' V 7 EXAMPLE 8 l7}8-hydroxy-5 ()-eszren-3-one benzozite a In the mannergiven in Example 1, hydrolyz ing 3 methoxy2,5(1 0)-estradien-17{3-olbenzoate, dissolved in methanol in the presence of oxalicacid, yielded17;?-

17fl-hydroxy-5(l0)estren-3-one henzoate is also obtained byesterifyingin the manner given in Example 2, l7fl-hydroxy-5(lO)-estren-3-one withbenzoyl chloride.

7 EXAMPLE 9 V V r 17,8-hydr0xy-5 (10)-estren-3-0ne phenylacetizte In themanner given in Example 1, 'hydrolyzing 3- methoxy 2,5 l0) estradien-17Bol 'phenylacetate, dissolved in methanol in the presenceof oxalic acid,yielded l7,8-hydroxy-5( l9) -estren-3-one phenylacetate.

EXAMPLE 10 l7,8Jtydr0xy 5(10)-estren-3-0ne Z-furoate A p 7 In the mannergiven in Example A 1, hydrolyzing 3- methoxy-2,5(lO)-estradien-l7B-ol2-furoate, dissolved in methanol :in the presence of oxalic acid yielded17,8-hydroxy-5(1()).-estren-3-one 2-furoate.

E d 17fi-hydroxy-5(10)-estren-3-one 2-furoate is also obtained byesterifying in the manner given in Example 2,17fi-hydroXy-5(10)-estren-3-one with 2-fnroyl chloride.

EXAMPLE l1 1 7i3-hydroxy-5 (10) -estren-3-0ne 1 7fi-acylates In the samemanner as given in Examples 1 through 10, other17B-hydroxy-5(10)-estren-3-one 17,8-acylates are obtained by hydrolyzingthe corresponding 3-methoxy- 2,5 (10)-estradien-l7/3-ol acylates inaqueous alcoholic solutions in the presence of oxalic acid or byesterification of l7f3-hydroxy-5(10)-estren-3-one with acid anhydridesor chlorides of organic carboxylic acids containing from one to eightcarbon atoms. Among the 17,8-acylates ofl7fl-hydroXy-5(10)-estren-3-ones thus obtained are: isobutyrate,isovalerate, hexanoate, heptanoate, octanoate, acid succinate, anisate,salicylate, the toluate, cinnarnate, gallate, benzenesnlfonate,para-chlorobenzenesulfonate, toluenesulfonate, benzenephosphonate,trimethylacetate, dichloroacetate, trichloroacetate, acid quinolinate,nicotinate, piperonate, acid tarti'ate, dihydrogencitrate, acid maleate,acid fumarate, crotonate, fl-rnethylcrotonate, o-chlorobenzoate,p-nitrobenzoate, o-chloro-p-nitrobenzoate, and the like.

It is to be understood that the invention is not to be i limited to theexact details of operation or exact compounds shown and described, asobvious modifications and equivalents Will be apparent to one skilled inthe art, and the invention is therefore to be limited only by the scopeof the appended claims.

d We claim: 1. 17,8-hydroxy-5(10)-estren-3-one hydrocarbon carboxylicacid acylates of the formula:

OHa

OAc

References Cited in the file of this patent UNITED STATES PATENTSMiescher Feb. 22, 1938 OTHER REFERENCES Birch: J. Chem. Soc. (London),1949, 2531-6.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTIUN Patent No.2,846,452 August 5, 1958 J Allan Campbell et al.

It is hereby certified that error appears in the printed specificationof the above numbered patent requiring correction and that the saidLetters Patent should read as corrected below.

Column 2, line 32, for "(10) estradien" read (lO)-estradienline 50, for"B-methylread B-methmcy- Signed and sealed this 12th day of May 1959.

(SEAL) Attest:

KARL H. AXLINE 7 ROBERT C. WATSON Attesting Oflicer Commissioner ofPatents

1. 17B-HYDROXY-5(10)-ESTREN-3-ONE HYDROCARBON CARBOXYLIC ACID ACYLATESOF THE FORMULA: